1. Field of the Invention
The present invention relates to a method for producing optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-amino acid ester. The present invention is useful for producing optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester.
2. Description of the Related Art
(S)-N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester with an inhibitory action against angiotensin converting enzyme is useful as therapeutic agents of deteriorated cardiovascular system, hypertension, cardiac function impairment and liver function impairment. Alternatively, the (R) form thereof with an inhibitory action of enkepharinase is useful as analgesic, antidiarrheic, and antacid (JP-A-2-161 and JP-A-8-59606). Methods for producing optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester having been known so far include a method comprising optically resolving racemic 2-acetylthiomethyl-3-phenylpropionic acid by using ephedrine and subjecting one of the resulting products to condensation with glycine benzyl ester and N, Nxe2x80x2-dicyclohexylcarbodiimide (JP-A-8-59606). According to the method, however, the efficiency of the optical resolution of 2-acetylthiomethyl-3-phenylpropionic acid with ephedrine is so low that the method is not practical. Furthermore, the method generates such an enormous volume of sulfur-containing wastes that the method cannot be said to be an industrially advantageous method.
It is an object of the present invention to provide a method for producing optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-amino acid ester, particularly optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester, in an inexpensive manner suitable for industrial production.
The present inventors have made investigations so as to overcome the problems. Consequently, the inventors have found a method for producing N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-amino acid ester, the method comprising subjecting optically active 2-hydroxymethyl-3-phenylpropionic acid and an amino acid ester to condensation to subsequently convert the hydroxyl group into an elimination group, and substituting the elimination group with an acetylthio group. Thus, the invention has been achieved.
More specifically, the invention relates to a method for producing an optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-amino acid ester, represented by the general formula (IV): 
wherein R1 represents hydrogen, an amino acid side chain or a protected amino acid side chain; R2 represents a linear or branched C1 to C18 alkyl group, or a benzyl group which may or may not have a substituent; AcS represents an acetylthio group; and * represents an optically active carbon atom, the method comprising subjecting optically active 2-hydroxymethyl-3-phenylpropionic acid, represented by the general formula (I): 
wherein * represents an optically active carbon atom, to reaction with an amino acid ester or a salt thereof for conversion into optically active N-(2-hydroxymethyl-1-oxo-3-phenylpropyl)-amino acid ester, represented by the general formula (II): 
wherein R1 and R2 independently represent the same as described above and * represents an optically active carbon atom; activating the hydroxyl group of the hydroxymethyl group at the 2-position for conversion into optically active N-acylamino acid ester, represented by the general formula (III): 
wherein R1 and R2 independently represent the same as described above; X represents chlorine, bromine, iodine, a linear, branched or cyclic C1-C6 alkylsulfonyloxy group which may or may not have a substituent, or a C6-C18 arylsulfonyloxy group; and * represents an optically active carbon atom; and further subjecting the resulting optically active N-acylamino acid ester to reaction with a thioacetate salt or thioacetic acid in the presence of a base.
The present invention is particularly useful for producing optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester. More specifically, the invention relates to a method for producing optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester, represented by the general formula (IV): 
wherein R1 represents hydrogen; R2 represents a benzyl group; AcS represents an acetylthio group; and * represents an optically active carbon atom, the method comprising subjecting optically active 2-hydroxymethyl-3-phenylpropionic acid, represented by the general formula (I): 
wherein * represents an optically active carbon atom, to reaction with glycine benzyl ester or a salt thereof for conversion into optically active N-(2-hydroxymethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester, represented by the general formula (II): 
wherein R1 represents hydrogen; R2 represents benzyl group; and * represents an optically active carbon atom; activating the hydroxymethyl group at the 2-position for conversion into optically active N-acylglycine benzyl ester, represented by the general formula (III): 
wherein X represents chlorine, bromine, iodine, a linear, branched or cyclic C1-C6 alkylsulfonyloxy group which may or may not have a substituent, or a C6-C18 arylsulfonyloxy group; R1 represents hydrogen; R2 represents a benzyl group; and * represents an optically active carbon atom; and further subjecting the resulting N-acylglycine benzyl ester to reaction with a thioacetate salt or thioacetic acid in the presence of a base.
According to the invention, the optically active carbon atom can be in the S configuration or in the R configuration.
Additionally, significant intermediates according to the method, namely the optically active N-(2-hydroxymethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester represented by the general formula (II) and the optically active N-acyl-glycine benzyl ester represented by the general formula (III) are also encompassed within the scope of the present invention.
The optically active 2-hydroxymethyl-3-phenylpropionic acid (I) for use as a raw material in accordance with the invention, can be prepared by optically resolving racemic 2-hydroxymethyl-3-phenylpropionic acid by using an optically active amine such as (1R,2S)-(+)-cis-1-amino-2-indanol (JP97-270680).
The amino acid in the amino acid ester or a salt thereof for use as the raw material in accordance with the invention includes glycine, phenylglycine, alanine, glutamine, asparagine, valine, leucine, isoleucine, proline, methionine, serine, threonine, phenylalanine, naphtylalanine, tyrosine, 3,4-dihydroxyphenylalanine, tryptophan, histidine, glutamic acid, aspartic acid, lysine, and arginine. These amino acids may satisfactorily have substituents at the side chains thereof. Examples of substituents include C1-C6 alkyl groups, C1-C6 alkoxy groups, a halogen group and a nitro group. Furthermore, any reactive functional group within the side chains is preferably protected with protective groups for use in peptide synthesis, for example ester-type protective groups such as methyl ester, ethyl ester, and benzyl ester for carboxyl group; acyl groups such as formyl group, acetyl group, trifluoroacetyl group, benzoyl group, t-butyloxycarbonyl group and benzyloxycarbonyl group for amino group; and ether-type protective groups such as benzyl ether and t-butyl ether and ester-type protective groups such as acetyl or benzoyl for hydroxyl group.
In the amino acid ester, xcex1-carboxyl group has been esterified preliminarily. The ester includes for example methyl ester, ethyl ester and benzyl ester. The ester may optionally have substituents. Examples of substituents include C1-C6 alkyl groups, C1-C6 alkoxy groups, a halogen group and a nitro group. Because the xcex1-carboxyl group of the amino acid in the final compound, namely N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-glycine benzyl ester as one of the objective compounds of the invention, is prepared in the form of benzyl ester, the amino acid ester is preferably in the form of benzyl ester. The amino acid ester in the objective compounds may satisfactorily be deprotected in a conventional manner.
The reaction of optically active 2-hydroxymethyl-3-phenylpropionic acid (I) with an amino acid ester to convert the phenylpropionic acid (I) into optically active N-(2-hydroxymethyl-1-oxo-3-phenylpropyl)-amino acid ester (II) is promoted by a condensation process for use in general peptide synthesis.
More specifically, optically active 2-hydroxymethyl-3-phenylpropionic acid (I) is subjected to reaction with an amino acid ester in the presence of a condensation agent in a solvent.
The condensation agent for use in the reaction includes N, Nxe2x80x2-dicyclohexylcarbodiimide, a water-soluble carbodiimide, carbonyldiimidazole, and diphenylphosphoryl azide. Glycine benzyl ester may be used in the free form or in the form of a salt with hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and the like. Use may be made of solvents such as hydrocarbon halides such as dichloromethane and chloroform; ethers such as tetrahydrofuran and methyl tert-butyl ether; acetate esters such as ethyl acetate and isopropyl acetate; nitrites such as acetonitrile; aromatic hydrocarbons such as toluene and xylene; dimethylformamide and dimethylsulfoxide.
Additionally, bases such as triethylamine, pyridine, N-methylmorpholine, and 4-dimethylaminopyridine may optionally be present concurrently in the reaction system. Still further, additives such as N-hydroxysuccinimide and 1-hydroxybenzotriazole may also be used.
The conversion of optically active N-(2-hydroxymethyl-1-oxo-3-phenylpropyl)-amino acid ester (II) into optically active N-acylamino acid ester (III) by activating the hydroxyl group of the hydroxymethyl group at 2-position of the amino acid ester (II) can be promoted by alkylsulfonation, arylsulfonation or halogenation or the like for general use in the activation of the hydroxyl group.
The hydroxyl group is alkylsulfonated or arylsulfonated by the action of an sulfonation agent in the presence of an activation base. The sulfonation agent includes methanesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, and trifluoromethanesulfonyl chloride. The activation base includes triethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine.
The hydroxyl group is halogenated via the action of halogenating agents such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, and phosphorus tribromide or via the action of halogenating agents, in the presence of triphenylphosphine, such as N-chlorosuccinimide, N-bromosuccinimide, bromide, carbon tetrachloride and carbon tetrabromide. Alternatively, the halogenation of the hydroxyl group comprises alkylsulfonating, arylsulfonating or haloformylating the hydroxyl group, and subsequently subjecting the resulting halogenated hydroxyl group to reaction with lithium chloride, lithium bromide, sodium bromide, potassium bromide, magnesium bromide, tetra-(n-butyl)ammonium bromide or sodium iodide.
The optically active 2-hydroxymethyl-3-phenylpropionic acid (I) can be converted into-optically active N-acylamino acid ester (III) at one step, by subjecting the 2-hydroxymethyl-3-phenylpropionic acid (I) to reaction with thionyl chloride or thionyl bromide or the like to convert the carboxyl group into an acid chloride and concurrently preparing the hydroxyl group into an elimination group such as halogen or sulfinyloxy-chloride group and subjecting the elimination group to reaction with amino acid ester.
The optically active N-acyl-amino acid ester (III) can be converted into optically active N-(2-acetylthiomethyl-1-oxo-3-phenylpropyl)-amino acid ester (IV), by subjecting the optically active N-acylamino acid ester (III) to reaction with a thioacetate salt or reaction with thioacetic acid in the presence of a base. The thioacetate salt includes potassium thioacetate, sodium thioacetate, lithium thioacetate, and cesium thioacetate.
For the aforementioned reaction, any inorganic base or organic base may be used in the co-existence of thioacetic acid; the inorganic base includes sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate; and the organic base includes triethylamine, pyridine, N-methylmorpholine, and diisopropylethylamine.
For the reaction, the thioacetic acid salt, thioacetic acid and base are used at 1.0 to 4.0 equivalents, preferably 1.0 to 2.0 equivalents. The solvent includes hydrocarbon halides such as dichloromethane and chloroform; ethers such as tetrahydrofuran and methyl tert-butyl ether; ketones such as acetone and 4-methyl-2-pentanone; acetate esters such as ethyl acetate and isopropyl acetate; nitrites such as acetonitrile; aromatic hydrocarbons such as toluene and xylene; and dimethylformamide and dimethylsulfoxide. The reaction temperature is 0 to 100xc2x0 C. preferably 20 to 60xc2x0 C.
The objective compound can be isolated, by removing impurities via procedures such as extraction after completion of the reaction and depositing the crystal in an appropriate solvent. Then, procedures for example column chromatography may also be conducted.
When amino acid side chains are protected, generally, deprotection is conducted finally by a general procedure. Thus, the objective compound can be obtained.